One-pot preparation of a benzoisoindolenine salt from a tetrahydronaphthalic anhydride

ABSTRACT

A method of effecting a one-pot conversion of a tetrahydronaphthalic anhydride to a benzisoindolenine salt is provided. The method comprises heating the tetrahydronaphthalic anhydride with a reagent mixture comprising ammonium nitrate.

FIELD OF THE INVENTION

The present application relates generally to an improved method of synthesizing naphthalocyanines. It has been developed primarily to reduce the cost of existing naphthalocyanine syntheses and to facilitate large-scale preparations of these compounds.

CROSS REFERENCE TO OTHER RELATED APPLICATIONS

The following applications have been filed by the Applicant simultaneously with this application:

-   -   IRB023US IRB025US

The disclosure of these co-pending applications are incorporated herein by reference. The above applications have been identified by their filing docket number, which will be substituted with the corresponding application number, once assigned.

The following patents or patent applications filed by the applicant or assignee of the present invention are hereby incorporated by cross-reference.

10/815621 10/815612 10/815630 10/815637 10/815638 10/815640 10/815642 7097094 7137549 10/815618 7156292 11738974 10/815635 10/815647 10/815634 7137566 7131596 7128265 7207485 7197374 7175089 10/815617 10/815620 7178719 10/815613 7207483 10/815619 10/815616 10/815614 11/488162 11/488163 11/488164 11/488167 11/488168 11/488165 11/488166 11/499748 10/815636 7128270 11/041650 11/041651 11/041652 11/041649 11/041610 11/041609 11/041626 11/041627 11/041624 11/041625 11/041556 11/041580 11/041723 11/041698 11/041648 10/815609 7150398 7159777 10/815610 7188769 7097106 7070110 7243849 11/480957 11764694 7204941 10/815624 10/815628 10/913375 10/913373 10/913374 10/913372 7138391 7153956 10/913380 10/913379 10/913376 7122076 7148345 11/172816 11/172815 11/172814 11/482990 11/482986 11/482985 11/583942 11/592990 60/851754 11/756624 11/566625 11/756626 11/756627 11/756629 11/756630 11/756631 7156289 7178718 7225979 11/712434 11/084796 11/084742 11/084806 09/575197 7079712 09/575123 6825945 09/575165 6813039 7190474 6987506 6824044 7038797 6980318 6816274 7102772 09/575186 6681045 6678499 6679420 6963845 6976220 6728000 7110126 7173722 6976035 6813558 6766942 6965454 6995859 7088459 6720985 09/609303 6922779 6978019 6847883 7131058 09/721895 09/607843 09/693690 6959298 6973450 7150404 6965882 7233924 09/575181 09/722174 7175079 7162259 6718061 10/291523 10/291471 7012710 6825956 10/291481 7222098 10/291825 10/291519 7031010 6972864 6862105 7009738 6989911 6982807 10/291576 6829387 6714678 6644545 6609653 6651879 10/291555 10/291510 10/291592 10/291542 7044363 7004390 6867880 7034953 6987581 7216224 10/291821 7162269 7162222 10/291822 10/291524 10/291553 6850931 6865570 6847961 10/685523 10/685583 7162442 10/685584 7159784 10/804034 10/793933 6889896 10/831232 7174056 6996274 7162088 10/943874 10/943872 10/944044 10/943942 10/944043 7167270 10/943877 6986459 10/954170 7181448 10/981626 10/981616 10/981627 7231293 7174329 10/992713 11/006536 7200591 11/020106 11/020260 11/020321 11/020319 11/026045 11/059696 11/051032 11/059674 11/107944 11/107941 11/082940 11/082815 11/082827 11/082829 6991153 6991154 11/124256 11/123136 11/154676 11/159196 11/182002 11/202251 11/202252 11/202253 11/203200 11/202218 11/206778 11/203424 11/222977 11/228450 11/227239 11/286334 7225402 11/349143 11/442428 11/442385 11/478590 11/487499 11/520170 11/603057 11/706964 11/739032 11739014 7068382 7007851 6957921 6457883 10/743671 7044381 11/203205 7094910 7091344 7122685 7038066 7099019 7062651 6789194 6789191 10/900129 10/900127 10/913350 10/982975 10/983029 11/331109 6644642 6502614 6622999 6669385 6827116 7011128 10/949307 6549935 6987573 6727996 6591884 6439706 6760119 09/575198 7064851 6826547 6290349 6428155 6785016 6831682 6741871 6927871 6980306 6965439 6840606 7036918 6977746 6970264 7068389 7093991 7190491 10/901154 10/932044 10/962412 7177054 10/962552 10/965733 10/965933 10/974742 10/982974 7180609 10/986375 11/107817 11/148238 11/149160 11/250465 7202959 11/653219 11/706309 11/730392 6982798 6870966 6822639 6474888 6627870 6724374 6788982 09/722141 6788293 6946672 6737591 7091960 09/693514 6792165 7105753 6795593 6980704 6768821 7132612 7041916 6797895 7015901 10/782894 7148644 10/778056 10/778058 10/778060 10/778059 10/778063 10/778062 10/778061 10/778057 7096199 10/917468 10/917467 10/917466 10/917465 7218978 7245294 10/948253 7187370 10/917436 10/943856 10/919379 7019319 10/943878 10/943849 7043096 7148499 11/144840 11/155556 11/155557 11/193481 11/193435 11/193482 11/193479 11/255941 11/281671 11/298474 7245760 11/488832 11/495814 11/495823 11/495822 11/495821 11/495820 11/653242 11/754370 60911260 7055739 7233320 6830196 6832717 7182247 7120853 7082562 6843420 10/291718 6789731 7057608 6766944 6766945 10/291715 10/291559 10/291660 10/531734 10/409864 7108192 10/537159 7111791 7077333 6983878 10/786631 7134598 10/893372 6929186 6994264 7017826 7014123 7134601 7150396 10/971146 7017823 7025276 10/990459 7080780 11/074802 11/442366 11749158 10/492169 10/492152 10/492168 10/492161 10/492154 10/502575 10/531229 10/683151 10/531733 10/683040 10/510391 10/510392 10/778090 6957768 09/575172 7170499 7106888 7123239 6982701 6982703 7227527 6786397 6947027 6975299 7139431 7048178 7118025 6839053 7015900 7010147 7133557 6914593 10/291546 6938826 10/913340 7123245 6992662 7190346 11/074800 11/074782 11/074777 11/075917 7221781 11/102843 7213756 11/188016 7180507 11/202112 11/442114 11/737094 11/753570 60/829869 60/829871 60/829873 11/672522 11/672950 11/672947 11/672891 11/672954 11/672533 11754310 11754321 11754320 11/754319 11/754318 11/754317 11/754316 11/754315 11/754314 11/754313 11/754312 11/754311 11/743657 6454482 6808330 6527365 6474773 6550997 7093923 6957923 7131724 10/949288 7168867 7125098 11/706966 11/185722 11/181754 7188930

BACKGROUND OF THE INVENTION

We have described previously the use of naphthalocyanines as IR-absorbing dyes. Naphthalocyanines, and particularly gallium naphthalocyanines, have low absorption in the visible range and intense absorption in the near-IR region (750-810 nm). Accordingly, naphthalocyanines are attractive compounds for use in invisible inks. The Applicant's U.S. Pat. Nos. 7,148,345 and 7,122,076 (the contents of which are herein incorporated by reference) describe in detail the use of naphthalocyanine dyes in the formulation of inks suitable for printing invisible (or barely visible) coded data onto a substrate. Detection of the coded data by an optical sensing device can be used to invoke a response in a remote computer system. Hence, the substrate is interactive by virtue of the coded data printed thereon.

The Applicant's netpage and Hyperlabel® systems, which makes use of interactive substrates printed with coded data, are described extensively in the cross-referenced patents and patent applications above (the contents of which are herein incorporated by reference).

In the anticipation of widespread adoption of netpage and Hyperlabel® technologies, there exists a considerable need to develop efficient syntheses of dyes suitable for use in inks for printing coded data. As foreshadowed above, naphthalocyanines and especially gallium naphthalocyanines are excellent candidates for such dyes and, as a consequence, there is a growing need to synthesize naphthalocyanines efficiently and in high yield on a large scale.

Naphthalocyanines are challenging compounds to synthesize on a large-scale. In U.S. Pat. Nos. 7,148,345 and 7,122,076, we described an efficient route to naphthalocyanines via macrocyclization of naphthalene-2,3-dicarbonitrile. Scheme 1 shows a route to the sulfonated gallium naphthalocyanine 1 from naphthalene-2,3-dicarbonitrile 2, as described in U.S. Pat. No. 7,148,345.

However, a problem with this route to naphthalocyanines is that the starting material 2 is expensive. Furthermore, naphthalene-2,3-dicarbonitrile 2 is prepared from two expensive building blocks: tetrabromo-o-xylene 3 and fumaronitrile 4, neither of which can be readily prepared in multi-kilogram quantities.

Accordingly, if naphthalocyanines are to be used in large-scale applications, there is a need to improve on existing syntheses.

SUMMARY OF THE INVENTION

In a first aspect, there is provided a method of preparing a naphthalocyanine comprising the steps of:

-   -   (i) providing a tetrahydronaphthalic anhydride;     -   (ii) converting said tetrahydronaphthalic anhydride to a         benzisoindolenine; and     -   (iii) macrocyclizing said benzisoindolenine to form a         naphthalocyanine.         Optionally, the tetrahydronaphthalic anhydride is of formula         (I):

wherein:

-   R₁, R₂, R₃ and R₄ are each independently selected from hydrogen,     hydroxyl, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino,     di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro,     C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl,     C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl,     C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl,     C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl.

Optionally, R₁, R₂, R₃ and R₄ are all hydrogen.

Optionally, step (ii) comprises a one-pot conversion from the tetrahydronaphthalic anhydride to a benzisoindolenine salt. This one-pot conversion facilitates synthesis of naphthalocyanines via the route described above and greatly improves yields and scalability.

Optionally, the benzisoindolenine salt is a nitrate salt although other salts (e.g. benzene sulfonate salt) are of course within the scope of the present invention.

Optionally, the one-pot conversion is effected by heating with a reagent mixture comprising ammonium nitrate.

Optionally, the reagent mixture comprises at least 2 equivalents of ammonium nitrate with respect to the tetrahydronaphthalic anhydride.

Optionally, the reagent mixture comprises urea.

Optionally, the reagent mixture comprises at least one further ammonium salt.

Optionally, the further ammonium salt is selected from: ammonium sulfate and ammonium benzenesulfonate

Optionally, the reagent mixture comprises a catalytic amount of ammonium molybdate.

Optionally, the heating is within a temperature range of 150 to 200° C.

The reaction may be performed in the presence of or in the absence of a solvent. Optionally, heating is in the presence of an aromatic solvent. Examples of suitable solvents are nitrobenzene, biphenyl, diphenyl ether, mesitylene, anisole, phenetole, dichlorobenzene, trichlorobenzene and mixtures thereof.

Optionally, the benzisoindolenine is liberated from the benzisoindolenine salt using a base. Sodium methoxide is an example of a suitable base although the skilled person will be readily aware of other suitable bases.

Optionally, the benzisoindolenine is of formula (II):

wherein:

-   R₁, R₂, R₃ and R₄ are each independently selected from hydrogen,     hydroxyl, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino,     di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro,     C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl,     C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl,     C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl,     C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl.

Optionally, the naphthalocyanine is of formula (III):

wherein:

-   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅ and     R₁₆ are each independently selected from hydrogen, hydroxyl,     C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino,     di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro,     C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl,     C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl,     C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl,     C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl; -   M is absent or selected from Si(A¹)(A²), Ge(A¹)(A²), Ga(A¹), Mg,     Al(A¹), TiO, Ti(A¹)(A²), ZrO, Zr(A¹)(A²), VO, V(A¹)(A²), Mn, Mn(A¹),     Fe, Fe(A¹), Co, Ni, Cu, Zn, Sn, Sn(¹)(A²), Pb, Pb(A¹)(A²), Pd and     Pt; -   A¹ and A² are axial ligands, which may be the same or different, and     are selected from —OH, halogen, or —OR^(q); -   R^(q) is selected from C₁₋₁₆alkyl, C₅₋₂₀aryl, C₅₋₂₀arylalkyl,     C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl or Si(R^(x))(R^(y))(R^(z));     and -   R^(x), R^(y) and R^(z) may be the same or different and are selected     from C₁₋₂₀alkyl, C₅₋₂₀aryl, C₅₋₂₀arylalkyl, C₁₋₂₀alkoxy,     C₅₋₂₀aryloxy or C₅₋₂₀arylalkoxy;

Optionally, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are all hydrogen.

Optionally, M is Ga(A¹), such as Ga(OCH₂CH₂OCH₂CH₂OCH₂CH₂OMe); that is where R^(q) is CH₂CH₂OCH₂CH₂OCH₂CH₂OMe. For the avoidance of doubt, ethers such as CH₂CH₂OCH₂CH₂OCH₂CH₂OMe fall within the definition of alkyl groups as specified hereinbelow. Gallium compounds are preferred since they have excellent lightfastness, strong absorption in the near-IR region, and are virtually invisible to the human eye when printed on a page.

Optionally, step (iii) comprises heating the benzisoindolenine in the presence of a metal compound, such as AlCl₃ or GaCl₃ or a corresponding metal alkoxide. The reaction may be performed in the absence of or in the presence of a suitable solvent, such as toluene, nitrobenzene etc. When a metal alkoxide is used, the reaction may be catalyzed with a suitable base, such as sodium methoxide. Alcohols, such as triethylene glycol monomethyl ether or glycol may also be present to assist with naphthalocyanine formation. These alcohols may end up as the axial ligand of the naphthalocyanine or they may be cleaved from the metal under the reaction conditions. The skilled person will readily be able to optimize the conditions for naphthalocyanine formation from the benzisoindolenine.

Optionally, the method further comprises the step of sulfonating said naphthalocyanine. Sulfonate groups are useful for solubilizing the naphthalocyanines in ink formulations, as described in our earlier U.S. Pat. Nos. 7,148,345 and 7,122,076.

In a second aspect, there is provided a method of effecting a one-pot conversion of a tetrahydronaphthalic anhydride to a benzisoindolenine salt, said method comprising heating said tetrahydronaphthalic anhydride with a reagent mixture comprising ammonium nitrate.

This transformation advantageously obviates a separate dehydrogenation step to form the naphthalene ring system. The ammonium nitrate performs the dual functions of oxidation (dehydrogenation) and isoindolenine formation.

The isoindolenine salts generated according to the second aspect may be used in the synthesis of naphthalocyanines. Hence, this key reaction provides a significant improvement in routes to naphthalocyanines.

In general, optional features of this second aspect mirror the optional features described above in respect of the first aspect.

In a third aspect, there is provided a method of preparing a sultine of formula (V) from a dihalogeno compound of formula (IV)

the method comprising reacting the dihalogeno compound (IV) with a hydroxymethanesulfinate salt in a DMSO solvent so as to prepare the sultine (V); wherein:

-   R₁, R₂, R₃ and R₄ are each independently selected from hydrogen,     hydroxyl, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino,     di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro,     C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl,     C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl,     C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl,     C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl;     and -   X is Cl, Br or I.

The method according to the third aspect surprisingly minimizes polymeric by-products and improves yields, when compared to literature methods for this reaction employing DMF as the solvent. These advantages are amplified when the reaction is performed on a large scale (e.g. at least 0.3 molar, at least 0.4 molar or at least 0.5 molar scale).

Optionally, Nal is used to catalyze the coupling reactions when X is Cl or Br.

Optionally, a metal carbonate base (e.g. Na₂CO₃, K₂CO₃, Cs₂CO₃ etc) is present.

Optionally, the hydroxymethanesulfinate salt is sodium hydroxymethanesulfinate (Rongalite™).

Optionally, R₁, R₂, R₃ and R₄ are all hydrogen.

Optionally, the method comprises the further step of reacting the sultine (V) with an olefin at elevated temperature (e.g. about 80° C.) to generate a Diels-Alder adduct.

Optionally, the olefin is maleic anhydride and said Diels-Alder adduct is a tetrahydronaphthalic anhydride.

Optionally, the tetrahydronaphthalic anhydride is used as a precursor for naphthalocyanine synthesis, as described herein.

Optionally, the naphthalocyanine synthesis proceeds via conversion of the tetrahydronaphthalic anhydride to a benzisoindolenine, as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in detail with reference to the following drawings, in which:

FIG. 1 is a ¹H NMR spectrum of the crude sultine 10 in d₆-DMSO;

FIG. 2 is a ¹H NMR spectrum of the anhydride 8 in d₆-DMSO;

FIG. 3 is a ¹H NMR spectrum of the crude benzisoindolenine salt 12 in d₆-DMSO;

FIG. 4 is an expansion of the aromatic region of the ¹H NMR spectrum shown in FIG. 3;

FIG. 5 is a ¹H NMR spectrum of the benzisoindolenine 7 in d₆-DMSO;

FIG. 6 is an expansion of the aromatic region of the ¹H NMR spectrum shown in FIG. 5; and

FIG. 7 is a UV-VIS spectrum of naphthalocyanatogallium methoxytriethyleneoxide in NMP.

DETAILED DESCRIPTION

As an alternative to dicarbonitriles, the general class of phthalocyanines is known to be prepared from isoindolenines. In U.S. Pat. No. 7,148,345, we proposed the benzisoindolenine 5 as a possible precursor to naphthalocyanines.

However, efficient syntheses of the benzisoindolenine 5 were unknown in the literature, and it was hitherto understood that dicarbonitriles, such as naphthalene-2,3-dicarbonitrile 2, were the only viable route to naphthalocyanines.

Nevertheless, with the potentially prohibitive cost of naphthalene-2,3-dicarbonitrile 2, the present inventors sought to explore a new route to the benzisoindolenine 5, as outlined in Scheme 2.

Tetrahydronaphthalic anhydride 6 was an attractive starting point, because this is a known Diels-Alder adduct which may be synthesized via the route shown in Scheme 3.

Referring to Scheme 2l, it was hoped that the conversion of naphthalic anhydride 7 to the benzisoindolenine 5 would proceed analogously to the known conversion of phthalic anhydride to the isoindolenine 8, as described in WO98/31667.

However, a number of problems remained with the route outlined in Scheme 2. Firstly, the dehydrogenation of tetrahydronaphthalic anhydride 6 typically requires high temperature catalysis. Under these conditions, tetrahydronaphthalic anhydride 6 readily sublimes resulting in very poor yields. Secondly, the preparation of tetrahydronaphthalic anhydride 6 on a large scale was not known. Whilst a number of small-scale routes to this compound were known in the literature, these generally suffered either from poor yields or scalability problems.

The use of sultines as diene precursors is well known and 1,4-dihydro-2,3-benzoxathiin-3-oxide 10 has been used in a synthesis of 6 on a small scale (Hoey, M. D.; Dittmer, D. A. J. Org. Chem. 1991, 56, 1947-1948). As shown in Scheme 4, this route commences with the relatively inexpensive dichloro-o-xylene 11, but the feasibility of scaling up this reaction sequence is limited by the formation of undesirable polymeric by-products in the sultine-forming step. The formation of these by-products makes reproducible production of 6 in high purity and high yield difficult.

Nevertheless, the route outlined in Scheme 4 is potentially attractive from a cost standpoint, since dichloro-o-xylene 11 and maleic anhydride are both inexpensive materials.

Whilst the reaction sequence shown in Schemes 4 and 2 present significant synthetic challenges, the present inventors have surprisingly found that, using modified reaction conditions, the benzisoindolenine 5 can be generated on a large scale and in high yield. Hence, the present invention enables the production of naphthalocyanines from inexpensive starting materials, and represents a significant cost improvement over known syntheses, which start from napthalene-2,3-dicarbonitrile 2.

Referring to Scheme 5, there is shown a route to the benzisoindolenine 5, which incorporates two synthetic improvements in accordance with the present invention.

Unexpectedly, it was found that by using DMSO as the reaction solvent in the conversion of 11 into 10, the reaction rate and selectively for the formation of sultine 10 increases significantly. This is in contrast to known conditions (Hoey, M. D.; Dittmer, D. A. J. Org. Chem. 1991, 56, 1947-1948) employing DMF as the solvent, where the formation of undesirable polymeric side-products is a major problem, especially on a large scale. Accordingly, the present invention provides a significant improvement in the synthesis of tetrahydronaphthalic anhydride 6.

The present invention also provides a significant improvement in the conversion of tetrahydronaphthalic anhydride 6 to the benzisoindolenine 5. Surprisingly, it was found that the ammonium nitrate used for this step readily effects oxidation of the saturated ring system as well as converting the anhydride to the isoindolenine. Conversion to a tetrahydroisoindolenine was expected to proceed smoothly, in accordance with the isoindolenine similar systems described in WO98/31667. However, concomitant dehydrogenation under these reaction conditions advantageously provided a direct one-pot route from the tetrahydronaphthalic anhydride 6 to the benzisoindolenine salt 12. This avoids problematic and low-yielding dehydrogenation of the tetrahydronaphthalic anhydride 6 in a separate step. Subsequent treatment of the salt 12 with a suitable base, such as sodium methoxide, liberates the benzisoindolenine 5. As a result of these improvements, the entire reaction sequence from 11 to 5 is very conveniently carried out, and employs inexpensive starting materials and reagents (Scheme 5).

The benzisoindolenine 5 may be converted into any required naphthalocyanine using known conditions. For example, the preparation of gallium naphthalocyanine from benzisoindolenine 5 is exemplified herein. Subsequent manipulation of the naphthalocyanine macrocycle may also be performed in accordance with known protocols. For example, sulfonation may be performed using oleum, as described in U.S. Pat. Nos. 7,148,345 and 7,122,076.

Hitherto, the use of tetrahydronaphthalic anhydride 6 as a building block for naphthalocyanine synthesis had not previously been reported. However, it has now been shown that tetrahydronaphthalic anhydride 6 is a viable intermediate in the synthesis of these important compounds. Moreover, it is understood by the present inventors that the route shown in Scheme 5 represents the most cost-effective synthesis of benzisoindolenines 5.

The term “aryl” is used herein to refer to an aromatic group, such as phenyl, naphthyl or triptycenyl. C₆₋₁₂aryl, for example, refers to an aromatic group having from 6 to 12 carbon atoms, excluding any substituents. The term “arylene”, of course, refers to divalent groups corresponding to the monovalent aryl groups described above. Any reference to aryl implicitly includes arylene, where appropriate.

The term “heteroaryl” refers to an aryl group, where 1, 2, 3 or 4 carbon atoms are replaced by a heteroatom selected from N, O or S. Examples of heteroaryl (or heteroaromatic) groups include pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, indolyl, isoindolyl, furanyl, thiophenyl, pyrrolyl, thiazolyll, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, isoxazolonyl, piperazinyl, pyrimidinyl, piperidinyl, morpholinyl, pyrrolidinyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, benzopyrimidinyl, benzotriazole, quinoxalinyl, pyridazyl, coumarinyl etc. The term “heteroarylene”, of course, refers to divalent groups corresponding to the monovalent heteroaryl groups described above. Any reference to heteroaryl implicitly includes heteroarylene, where appropriate.

Unless specifically stated otherwise, aryl and heteroaryl groups may be optionally substituted with 1, 2, 3, 4 or 5 of the substituents described below.

Where reference is made to optionally substituted groups (e.g. in connection with aryl groups or heteroaryl groups), the optional substituent(s) are independently selected from C₁₋₈alkyl, C₁₋₈alkoxy, —(OCH₂CH₂)₃OR^(d) (wherein d is an integer from 2 to 5000 and R^(d) is H, C₁₋₈alkyl or C(O)C₁₋₈alkyl), cyano, halogen, amino, hydroxyl, thiol, —SR^(v), —NR^(u)R^(v), nitro, phenyl, phenoxy, —CO₂R^(v), —C(O)R^(v), —OCOR^(v), —SO₂R^(v), —OSO₂R^(v), —SO₂OR^(v), —NHC(O)R^(v), —CONR^(u)R^(v), —CONR^(u)R^(v), —SO₂NR^(u)R^(v), wherein R^(u) and R^(v) are independently selected from hydrogen, C₁₋₂₀alkyl, phenyl or phenyl-C₁₋₈alkyl (e.g. benzyl). Where, for example, a group contains more than one substituent, different substituents can have different R^(u) or R^(v) groups.

The term “alkyl” is used herein to refer to alkyl groups in both straight and branched forms. Unless stated otherwise, the alkyl group may be interrupted with 1, 2, 3 or 4 heteroatoms selected from O, NH or S. Unless stated otherwise, the alkyl group may also be interrupted with 1, 2 or 3 double and/or triple bonds. However, the term “alkyl” usually refers to alkyl groups having double or triple bond interruptions. Where “alkenyl” groups are specifically mentioned, this is not intended to be construed as a limitation on the definition of “alkyl” above.

Where reference is made to, for example, C₁₋₂₀alkyl, it is meant the alkyl group may contain any number of carbon atoms between 1 and 20. Unless specifically stated otherwise, any reference to “alkyl” means C₁₋₂₀alkyl, preferably C₁₋₁₂alkyl or C₁₋₆alkyl.

The term “alkyl” also includes cycloalkyl groups. As used herein, the term “cycloalkyl” includes cycloalkyl, polycycloalkyl, and cycloalkenyl groups, as well as combinations of these with linear alkyl groups, such as cycloalkyalkyl groups. The cycloalkyl group may be interrupted with 1, 2 or 3 heteroatoms selected from O, N or S. However, the term “cycloalkyl” usually refers to cycloalkyl groups having no heteroatom interruptions. Examples of cycloalkyl groups include cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexylmethyl and adamantyl groups.

The term “arylalkyl” refers to groups such as benzyl, phenylethyl and naphthylmethyl.

The term “halogen” or “halo” is used herein to refer to any of fluorine, chlorine, bromine and iodine. Usually, however, halogen refers to chlorine or fluorine substituents.

Where reference is made herein to “a naphthalocyanine”, “a benzisoindolenine”, “a tetrahydronaphthalic anhydride” etc, this is understood to be a reference to the general class of compounds embodied by these generic names, and is not intended to refer to any one specific compound. References to specific compounds are accompanied with a reference numeral.

Chiral compounds described herein have not been given stereo-descriptors. However, when compounds may exist in stereoisomeric forms, then all possible stereoisomers and mixtures thereof are included (e.g. enantiomers, diastereomers and all combinations including racemic mixtures etc.).

Likewise, when compounds may exist in a number of regioisomeric or tautomeric forms, then all possible regioisomers, tautomers and mixtures thereof are included.

For the avoidance of doubt, the term “a” (or “an”), in phrases such as “comprising a”, means “at least one” and not “one and only one”. Where the term “at least one” is specifically used, this should not be construed as having a limitation on the definition of “a”.

Throughout the specification, the term “comprising”, or variations such as “comprise” or “comprises”, should be construed as including a stated element, integer or step, but not excluding any other element, integer or step.

The invention will now be described with reference to the following drawings and examples. However, it will of course be appreciated that this invention may be embodied in many other forms without departing from the scope of the invention, as defined in the accompanying claims.

EXAMPLE 1 1,4-dihydro-2,3-benzoxathiin-3-oxide 10

Sodium hydroxymethanesulfinate (Rongalite™) (180 g; 1.17 mol) was suspended in DMSO (400 mL) and left to stir for 10 min. before dichloro-o-xylene (102.5 g; 0.59 mol), potassium carbonate (121.4 g; 0.88 mol) and sodium iodide (1.1 g; 7 mmol) were added consecutively. More DMSO (112 mL) was used to rinse residual materials into the reaction mixture before the whole was allowed to stir at room temperature. The initial endothermic reaction became mildly exothermic after around 1 h causing the internal temperature to rise to ca. 32-33° C. The reaction was followed by TLC (ethyl acetate/hexane, 50:50) and found to be complete after 3 h. The reaction mixture was diluted with methanol/ethyl acetate (20:80; 400 mL) and the solids were filtered off, and washed with more methanol/ethyl acetate (20:80; 100 mL, 2×50 mL). The filtrate was transferred to a separating funnel and brine (1 L) was added. This caused more sodium chloride from the product mixture to precipitate out. The addition of water (200 mL) redissolved the sodium chloride. The mixture was shaken and the organic layer was separated and then the aqueous layer was extracted further with methanol/ethyl acetate (20:80; 200 mL, 150 mL, 250 mL). The combined extracts were dried (Na₂SO₄) and rotary evaporated (bath 37-38° C.). More solvent was removed under high vacuum to give the sultine 10 as a pale orange liquid (126 g) that was found by ¹H NMR spectroscopy to be relatively free of by-product but containing residual DMSO and ethyl acetate (FIG. 1).

EXAMPLE 2 Tetrahydronaphthalic Anhydride 6

The crude sultine from above (126 g) was diluted in trifluorotoluene (100 mL) and then added to a preheated (bath 80° C.) suspension of maleic anhydride (86 g; 0.88 mol) in trifluorotoluene (450 mL). The residual sultine was washed with more trifluorotoluene into the reaction mixture and then the final volume was made up to 970 mL. The reaction mixture was heated at 80° C. for 15 h, more maleic anhydride (28.7 g; 0.29 mol) was added and then heating was continued for a further 8 h until TLC showed that the sultine had been consumed. While still at 80° C., the solvent was removed by evaporation with a water aspirator and then the residual solvent was removed under high vacuum. The moist solid was triturated with methanol (200 mL) and filtered off, washing with more methanol (3×100 mL). The tetrahydronaphthalic anhydride 6 was obtained as a fine white crystalline solid (75.4 g; 64% from 10) after drying under high vacuum at 60-70° C. for 4 h.

The sultine was prepared from dichloro-o-xylene (31.9 g; 0.182 mol), as described in Example 2, and then reacted with maleic anhydride (26.8 g; 0.273 mol) in toluene (300 mL total volume) as described above. This afforded the tetrahydronaphthalc anhydride 6 as a white crystalline solid (23.5 g; 64%).

EXAMPLE 4 1-amino-3-iminobenz[f]isoindolenine Nitrate Salt 12

Urea (467 g; 7.78 mol) was added to a mechanically stirred mixture of ammonium sulfate (38.6 g; 0.29 mol), ammonium molybdate (1.8 g) and nitrobenzene (75 mL). The whole was heated with a heating mantle to ca. 130° C. (internal temperature) for 1 h causing the urea to melt. At this point the anhydride 6 (98.4 g; 0.49 mol) was added all at once as a solid. After 15 min ammonium nitrate (126.4 g; 1.58 mol) was added with stirring (internal temperature 140° C.) accompanied by substantial gas evolution. The reaction temperature was increased to 170-175° C. over 45 min and held there for 2 h 20 min. The viscous brown mixture was allowed to cool to ca. 100° C. and then methanol (400 mL) was slowly introduced while stirring. The resulting suspension was poured on a sintered glass funnel, using more methanol (100 mL) to rinse out the reaction flask. After removing most of the methanol by gravity filtration, the brown solid was sucked dry and then washed with more methanol (3×200 mL, 50 mL), air-dried overnight and dried under high vacuum in a warm water bath for 1.5 h. The benzisoindolenine salt 12 was obtained as a fine brown powder (154.6 g) and was found by NMR analysis to contain urea (5.43 ppm) and other salts (6.80 ppm). This material was used directly in the next step without further purification.

EXAMPLE 5 1-amino-3-iminobenz[f]isoindolenine 7

The crude nitrate salt 12 (154.6 g) was supported in acetone (400 mL) with cooling in an ice/water bath to 0° C. Sodium methoxide (25% in methanol; 284 ml; 1.3 mol) was slowly dropwise via a dropping funnel at such a rate as to maintain an internal temperature of 0-5° C. Upon completion of the addition, the reaction mixture was poured into cold water (2×2 L) in two 2 L conical flasks. The mixtures were then filtered on sintered glass funnels and the solids were washed thoroughly with water (250 mL; 200 mL for each funnel). The fine brown solids were air-dried over 2 days and then further dried under high vacuum to give the benzisoindolenine 5 as a fine brown powder (69.1 g; 73%).

EXAMPLE 6 Naphthalocyanatogallium Methoxytriethyleneoxide

Gallium chloride (15.7 g; 0.89 mol) was dissolved in anhydrous toluene (230 mL) in a 3-neck flask (1 L) equipped with a mechanical stirrer, heating mantle, thermometer, and distillation outlet. The resulting solution was cooled in an ice/water bath to 10° C. and then sodium methoxide in methanol (25%; 63 mL) was added slowly with stirring such that the internal temperature was maintained below 25° C. thereby affording a white precipitate. The mixture was then treated with triethylene glycol monomethyl ether (TEGMME: 190 mL) and then the whole was heated to distill off all the methanol and toluene (3 h). The mixture was then cooled to 90-100° C. (internal temperature) by removing the heating mantle and then the benzisoindolenine 5 from the previous step (69.0 g; 0.35 mol) was added all at once as a solid with the last traces being washed into the reaction vessel with diethyl ether (30 mL). The reaction mixture was then placed in the preheated heating mantle such that an internal temperature of 170° C. was established after 20 min. Stirring was then continued at 175-180° C. for a further 3 h during which time a dark green/brown colour appeared and the evolution of ammonia took place. The reaction mixture was allowed to cool to ca. 100° C. before diluting with DMF (100 mL) and filtering through a sintered glass funnel under gravity overnight. The moist filter cake was sucked dry and washed consecutively with DMF (80 mL), acetone (2×100 mL), water (2×100 mL), DMF (50 mL), acetone (2×50 mL; 100 mL) and diethyl ether (100 mL) with suction. After brief air drying, the product was dried under high vacuum at 60-70° C. to constant weight. Naphthalocyanatogallium methoxytriethyleneoxide was obtained as a microcrystalline dark blue/green solid (60.7 g; 76%); λ_(max) (NMP) 771 nm (FIG. 7). 

1. A method of effecting a one-pot conversion of a tetrahydronaphthalic anhydride to a benzisoindolenine salt, said method comprising heating said tetrahydronaphthalic anhydride with a reagent mixture comprising ammonium nitrate.
 2. The method of claim 1, wherein said tetrahydronaphthalic anhydride is of formula (I):

wherein: R₁, R₂, R₃ and R₄ are each independently selected from hydrogen, hydroxyl, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino, di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro, C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl, C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl, C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl, C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl.
 3. The method of claim 2, wherein R₁, R₂, R₃ and R₄ are all hydrogen.
 4. The method of claim 1, wherein said benzisoindolenine salt is a nitrate salt.
 5. The method of claim 1, wherein said reagent mixture comprises at least 2 equivalents of ammonium nitrate with respect to said tetrahydronaphthalic anhydride.
 6. The method of claim 1, wherein said reagent mixture comprises urea.
 7. The method of claim 1, wherein said reagent mixture comprises at least one further ammonium salt.
 8. The method of claim 7, wherein said at least one further ammonium salt is selected from: ammonium sulfate and ammonium benzenesulfonate.
 9. The method of claim 1, wherein said reagent mixture comprises a catalytic amount of ammonium molybdate.
 10. The method of claim 1, wherein said heating is within a temperature range of 150 to 200° C.
 11. The method of claim 10, wherein said heating is in the presence of solvent selected from the group comprising: nitrobenzene, diphenyl, diphenyl ether, mesitylene, anisole, phenetole, dichlorobenzene, trichlorobenzene and mixtures thereof.
 12. The method of claim 1, comprising the further step of liberating the corresponding benzisoindolenine from the benzisoindolenine salt using a base.
 13. The method of claim 12, wherein said benzisoindolenine is of formula (II):

wherein: R₁, R₂, R₃ and R₄ are each independently selected from hydrogen, hydroxyl, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino, di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro, C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl, C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl, C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl, C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl.
 14. The method of claim 12, further comprising the step of macrocyclizing said benzisoindolenine to form a naphthalocyanine.
 15. The method of claim 14, wherein said naphthalocyanine is of formula (III):

wherein: R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are each independently selected from hydrogen, hydroxyl, C₁₋₂₀alkyl, C₁₋₂₀alkoxy, amino, C₁₋₂₀alkylamino, di(C₁₋₂₀alkyl)amino, halogen, cyano, thiol, C₁₋₂₀alkylthio, nitro, C₁₋₂₀alkylcarboxy, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl, C₁₋₂₀alkylcarbonyloxy, C₁₋₂₀alkylcarbonylamino, C₅₋₂₀aryl, C₅₋₂₀arylalkyl, C₅₋₂₀aryloxy, C₅₋₂₀arylalkoxy, C₅₋₂₀heteroaryl, C₅₋₂₀heteroaryloxy, C₅₋₂₀heteroarylalkoxy or C₅₋₂₀heteroarylalkyl; M is absent or selected from Si(A¹)(A²), Ge(A¹)(A²), Ga(A¹), Mg, Al(A¹), TiO, Ti(A¹)(A²), ZrO, Zr(A¹)(A²), VO, V(A¹)(A²), Mn, Mn(A¹), Fe, Fe(A¹), Co, Ni, Cu, Zn, Sn, Sn(A¹)(A²), Pb, Pb(A¹)(A²), Pd and Pt; A¹ and A² are axial ligands, which may be the same or different, and are selected from —OH, halogen or —OR^(q); R^(q) is selected from C₁₋₁₆alkyl, C₅₋₂₀aryl, C₅₋₂₀arylalkyl, C₁₋₂₀alkylcarbonyl, C₁₋₂₀alkoxycarbonyl or Si(R^(x))(R^(y))(R^(z)); and R^(x), R^(y) and R^(z) may be the same or different and are selected from C₁₋₂₀alkyl, C₅₋₂₀aryl, C₅₋₂₀arylalkyl, C₁₋₂₀alkoxy, C₅₋₂₀aryloxy or C₅₋₂₀arylalkoxy.
 16. The method of claim 15, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ are all hydrogen.
 17. The method of claim 16, wherein M is Ga(A¹).
 18. The method of claim 14, wherein said macrocyclization comprises heating said benzisoindolenine in the presence of a metal compound. 